IPF is a chronic and progressive lung disease that results in respiratory failure and death. Median survival is about 2 to 4 years from diagnosis. The etiology of IPF remains unknown, but the disease is characterized by fibrotic interstitial infiltrates that are consistent with the histopathologic pattern of usual interstitial pneumonia. (Gross TJ et al. N Engl J Med (2001); 345:(7):517-525.) As interstitial fibrosis advances with accompanying distortion of lung architecture, the lung becomes less compliant, increasing the effort associated with breathing, leading to dyspnea. Typically, lung function declines slowly over time, but some patients experience rapid declines that can lead to hospitalization or death, particularly in later stages of the disease. (Martinez FJ et al. Ann Intern Med (2005) 142:963-967.)
In the United States, as many as 89,000 people are afflicted with IPF, with about 34,000 newly diagnosed annually. (Raghu G et al., Am J Respir Crit Care Med (2006) 174: (7):810-816.) Prevalence of IPF ranges from 14.0 to 42.7 cases per 100,000 persons and the annual incidence ranges from 6.8 to 16.3 cases per 100,000 persons, depending on the strictness of the diagnostic criteria employed. (Raghu G et al., supra.) The prevalence of IPF increases with age, with most IPF patients 60 years of age or older at the time of diagnosis. The disease is more common in men than in women (Fernandez Perez E R et al. Chest (2010) 137:(1):129-137.) with most patients current or former smokers. A familial form of IPF may account for as many as 20% of IPF cases. (Loyd JE, Eur Respir Rev (2008) 17:(109): 163-167.)
While the pathogenesis of IPF is not clearly defined, the disease is believed to be caused by repetitive epithelial injury. (Selman M et al. Ann Intern Med (2001) 134:136-151; Selman M. Proc Am Thorac Soc (2006) (4):364-372.) According to this hypothesis, alveolar cell injury and activation initiate a dysregulated, exaggerated fibrotic healing process characterized by myofibroblast proliferation and progressive deposition of extracellular matrix (ECM) in genetically susceptible individuals. (Selman M et al. (2001) supra; Selman M. (2006) supra.)
There are currently no FDA-approved drugs for the treatment of IPF. Recently conducted phase 3 clinical trials of pirfenidone, sildenafil, bosentan, etanercept, and interferon gamma-1 b have failed to demonstrate efficacy in their primary endpoints. N-acetyl cysteine (NAC), corticosteroids, and the immunosuppressive drugs cyclophosphamide and azathioprine are commonly prescribed, but there is little evidence that use of these drugs improves patient outcome or alters the natural course of the disease. (Collard HR et al. Chest (2004) 125: (6):2169-2174, Walter N et al, Proc Am Thorac Soc (2006) 3: (4):377-381.) In fact, the combination of prednisone, azathioprine, and NAC produced a worse outcome than NAC or placebo in a recent IPF study. (NIH News, Oct. 24, 2011.) Lung transplantation is the only treatment that improves survival (Walter, supra.), but most IPF patients are not eligible for transplantation because of their age or comorbid conditions. IPF patients usually are managed with supportive measures such as symptomatic treatment of cough and dyspnea, supplemental oxygen for hypoxemia, smoking cessation, pulmonary rehabilitation, and prophylaxis and control of respiratory tract infections.
The progressive and fatal course of IPF coupled with the absence of approved drugs underscore the need for new methods and agents to treat this devastating disease. The present invention meets this unmet medical need by providing novel methods and agents for use in treating IPF. In particular, the present invention provides agents and methods for reducing, stabilizing or reversing the progression and severity of IPF and for preventing or treating one or more symptoms of IPF by inhibiting connective tissue growth factor (CTGF) activity.